Relationships between Adipose Tissue and Cytokine Responses to a Randomized Controlled Exercise Training Intervention

Adipose-derived cytokines play a prominent role in mediating the metabolic consequences of obesity and excess body fat. Given this, we hypothesized that alterations in adipose tissue stores incurred with exercise training would be reflected in changes in systemic cytokine concentrations. The Studies of Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE), where pronounced changes in adipose tissue stores were observed in the absence of significant changes in dietary intake, provided an ideal setting in which to test this hypothesis. Participants were randomized to six months of inactivity or one of three types of aerobic exercise training regimens: low-amount-moderate- intensity, low-amount-vigorous-intensity, and high-amount-vigorous-intensity. Plasma samples were collected at baseline and two weeks after cessation of six months of exercise training or inactivity. In 189 participants, concentrations of seventeen cytokines were measured using Bio-Plex Cytokine Assays (BioRad, CA); ten additional cytokines were measured in sixty of these subjects. Of all cytokines tested, the only concentration changes that approached statistical significance were those for granulocyte monocyte-colony stimulating factor and vascular endothelial growth factor, which appeared to increase with training in the low-amount-high-intensity group only (P<0.05 for both cytokines). No response to exercise training was noted for any additional cytokine in any of the groups. No relationships were observed between changes in cytokine concentrations and changes in fat mass or other measures of body habitus. In contradiction to our hypothesis, despite significant alterations in body composition, exercise training produced limited cytokine responses. Originally published Metabolism, Vol. 57, No. 4, Apr 200

Dietary carbohydrate intake and high sensitivity C reactive protein in at-risk women and men

Background— The quality and quantity of dietary carbohydrate intake, measured as dietary glycemic load (GL), is associated with a number of cardiovascular disease (CVD) risk factors and, in healthy young women, is related to increased high sensitivity C-reactive protein (hsCRP) concentrations. Our objective was to determine if GL is related to hsCRP and other measures of CVD risk in a population of sedentary, overweight, dyslipidemic middle-aged women and men enrolled in an exercise intervention trial (STRRIDE). Methods— This was a cross-sectional evaluation of the relationships between measures of dietary carbohydrate intake, calculated from food frequency questionnaire data, and CVD risk factors, including plasma hsCRP, measured in 171 subjects. Results— After adjusting for energy intake, GL and other measures of carbohydrate intake were not independently related to hsCRP (P>0.05 for all). In analyses performed separately for each gender, only the quantity of carbohydrate intake was independently related to hsCRP (R2=0.28; P<0.04), and this relationship was present for women but not for men. The strongest relationship identified between GL and any CVD risk factor was for cardiorespiratory fitness (R2=0.12; P<0.02); an elevated GL was associated with a lower level of fitness in all subjects, and this relationship persisted even when the findings were adjusted for energy intake and gender (R2=0.48; P<0.03). Conclusions— In middle-aged, sedentary, overweight to mildly obese, dyslipidemic individuals, consuming a diet with a low GL is associated with better cardiorespiratory fitness. Our findings suggest that the current literature relating carbohydrate intake and hsCRP should be viewed with skepticism, especially in the extension to at-risk populations that include men. Originally published American Heart Journal, Vol. 154, No. 5, Nov 200

GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer's Disease Models.

NMDA receptors (NMDARs) play subunit-specific roles in synaptic function and are implicated in neuropsychiatric and neurodegenerative disorders. However, the in vivo consequences and therapeutic potential of pharmacologically enhancing NMDAR function via allosteric modulation are largely unknown. We examine the in vivo effects of GNE-0723, a positive allosteric modulator of GluN2A-subunit-containing NMDARs, on brain network and cognitive functions in mouse models of Dravet syndrome (DS) and Alzheimer's disease (AD). GNE-0723 use dependently potentiates synaptic NMDA receptor currents and reduces brain oscillation power with a predominant effect on low-frequency (12-20 Hz) oscillations. Interestingly, DS and AD mouse models display aberrant low-frequency oscillatory power that is tightly correlated with network hypersynchrony. GNE-0723 treatment reduces aberrant low-frequency oscillations and epileptiform discharges and improves cognitive functions in DS and AD mouse models. GluN2A-subunit-containing NMDAR enhancers may have therapeutic benefits in brain disorders with network hypersynchrony and cognitive impairments

Effects of exercise training alone vs a combined exercise and nutritional lifestyle intervention on glucose homeostasis in prediabetic individuals: a randomised controlled trial

Although the Diabetes Prevention Program (DPP) established lifestyle changes (diet, exercise and weight loss) as the ‘gold standard’ preventive therapy for diabetes, the relative contribution of exercise alone to the overall utility of the combined diet and exercise effect of DPP is unknown; furthermore, the optimal intensity of exercise for preventing progression to diabetes remains very controversial. To establish clinical efficacy, we undertook a study (2009 to 2013) to determine: how much of the effect on measures of glucose homeostasis of a 6 month programme modelled after the first 6 months of the DPP is due to exercise alone; whether moderate- or vigorous-intensity exercise is better for improving glucose homeostasis; and to what extent amount of exercise is a contributor to improving glucose control. The primary outcome was improvement in fasting plasma glucose, with improvement in plasma glucose AUC response to an OGTT as the major secondary outcome

Effects of exercise amount and intensity versus a combined exercise and lifestyle intervention on metabolic syndrome in adults with prediabetes: a STRRIDE-PD randomized trial

The purpose of this secondary analysis was to determine what portion of the effects of a Diabetes Prevention Program-like intervention on metabolic syndrome (MetS) could be achieved with exercise alone, as well as to determine the relative importance of exercise intensity and amount to the total exercise effect on MetS. Sedentary, overweight adults with prediabetes were randomly assigned to one of four 6-month interventions: 1) low-amount/moderate-intensity (10 kcal/kg/week at 50% peak V˙O2); 2) high-amount/moderate-intensity (16 kcal/kg/week at 50% peak V˙O2); 3) high-amount/vigorous-intensity (16 kcal/kg/week at 75% peak V˙O2); or 4) diet (7% weight loss) plus low-amount/moderate-intensity (10 kcal/kg/week at 50% peak V˙O2). The primary outcome of this secondary analysis was change in the MetS z-score. A total of 130 participants had complete data for all five Adult Treatment Panel (ATP) III MetS criteria. The diet-and-exercise group statistically outperformed the MetS z-score and the ATP III score compared to the exercise alone group. Aerobic exercise alone achieved 24%–50% of the total effect of the combined diet-and-exercise intervention on the MetS score. Low-amount moderate-intensity exercise quantitatively performed equal to or better than the interventions of high-amount moderate-intensity or high-amount vigorous-intensity exercise in improving the MetS score. The combined diet-and-exercise intervention remains more efficacious in improving the MetS z-score. However, all three exercise interventions alone showed improvements in the MetS z-score, suggesting that a modest amount of moderate-intensity exercise is all that is required to achieve approximately half the effect of a diet-and-exercise intervention on the MetS.Clinical Trial Registration:clinicaltrials.gov, identifier NCT00962962

The cellular and synaptic architecture of the mechanosensory dorsal horn

The deep dorsal horn is a poorly characterized spinal cord region implicated in processing low-threshold mechanoreceptor (LTMR) information. We report an array of mouse genetic tools for defining neuronal components and functions of the dorsal horn LTMR-recipient zone (LTMR-RZ), a role for LTMR-RZ processing in tactile perception, and the basic logic of LTMR-RZ organization. We found an unexpectedly high degree of neuronal diversity in the LTMR-RZ: seven excitatory and four inhibitory subtypes of interneurons exhibiting unique morphological, physiological, and synaptic properties. Remarkably, LTMRs form synapses on between four and 11 LTMR-RZ interneuron subtypes, while each LTMR-RZ interneuron subtype samples inputs from at least one to three LTMR classes, as well as spinal cord interneurons and corticospinal neurons. Thus, the LTMR-RZ is a somatosensory processing region endowed with a neuronal complexity that rivals the retina and functions to pattern the activity of ascending touch pathways that underlie tactile perception

Respiratory plasticity in response to changes in oxygen supply and demand

Aerobic organisms maintain O2 homeostasis by responding to changes in O2 supply and demand in both short and long time domains. In this review, we introduce several specific examples of respiratory plasticity induced by chronic changes in O2 supply (environmental hypoxia or hyperoxia) and demand (exercise-induced and temperature-induced changes in aerobic metabolism). These studies reveal that plasticity occurs throughout the respiratory system, including modifications to the gas exchanger, respiratory pigments, respiratory muscles, and the neural control systems responsible for ventilating the gas exchanger. While some of these responses appear appropriate (e.g., increases in lung surface area, blood O2 capacity, and pulmonary ventilation in hypoxia), other responses are potentially harmful (e.g., increased muscle fatigability). Thus, it may be difficult to predict whole-animal performance based on the plasticity of a single system. Moreover, plastic responses may differ quantitatively and qualitatively at different developmental stages. Much of the current research in this field is focused on identifying the cellular and molecular mechanisms underlying respiratory plasticity. These studies suggest that a few key molecules, such as hypoxia inducible factor (HIF) and erythropoietin, may be involved in the expression of diverse forms of plasticity within and across species. Studying the various ways in which animals respond to respiratory challenges will enable a better understanding of the integrative response to chronic changes in O2 supply and deman

Viral Linkage in HIV-1 Seroconverters and Their Partners in an HIV-1 Prevention Clinical Trial

Characterization of viruses in HIV-1 transmission pairs will help identify biological determinants of infectiousness and evaluate candidate interventions to reduce transmission. Although HIV-1 sequencing is frequently used to substantiate linkage between newly HIV-1 infected individuals and their sexual partners in epidemiologic and forensic studies, viral sequencing is seldom applied in HIV-1 prevention trials. The Partners in Prevention HSV/HIV Transmission Study (ClinicalTrials.gov #NCT00194519) was a prospective randomized placebo-controlled trial that enrolled serodiscordant heterosexual couples to determine the efficacy of genital herpes suppression in reducing HIV-1 transmission; as part of the study analysis, HIV-1 sequences were examined for genetic linkage between seroconverters and their enrolled partners.We obtained partial consensus HIV-1 env and gag sequences from blood plasma for 151 transmission pairs and performed deep sequencing of env in some cases. We analyzed sequences with phylogenetic techniques and developed a Bayesian algorithm to evaluate the probability of linkage. For linkage, we required monophyletic clustering between enrolled partners' sequences and a Bayesian posterior probability of ≥ 50%. Adjudicators classified each seroconversion, finding 108 (71.5%) linked, 40 (26.5%) unlinked, and 3 (2.0%) indeterminate transmissions, with linkage determined by consensus env sequencing in 91 (84%). Male seroconverters had a higher frequency of unlinked transmissions than female seroconverters. The likelihood of transmission from the enrolled partner was related to time on study, with increasing numbers of unlinked transmissions occurring after longer observation periods. Finally, baseline viral load was found to be significantly higher among linked transmitters.In this first use of HIV-1 sequencing to establish endpoints in a large clinical trial, more than one-fourth of transmissions were unlinked to the enrolled partner, illustrating the relevance of these methods in the design of future HIV-1 prevention trials in serodiscordant couples. A hierarchy of sequencing techniques, analysis methods, and expert adjudication contributed to the linkage determination process

Treatment of Periodontitis by Local Administration of Minocycline Microspheres: A Controlled Trial

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141491/1/jper1535.pd